Traumatic injuries and age-related degenerative diseases associated with articular cartilage (AC) can result in significant patient morbidity and lead to the development of osteoarthritis. The Centers for Disease Control and Prevention estimates that nearly 67 million (25%) of US adults will have clinically-diagnosed arthritis by 2030, making it the nation's leading cause of disability. Because of the avascular nature and limited potential for growth and self-repair, the treatment of articular cartilage damage remains one of the most challenging topics in orthopedic healthcare. The social and economic implications of repairing or regenerating injured AC tissues either indefinitely or until the patient reaches the age at which total joint replacement is appropriate are enormous. The goal of this project is to design synthetic AC tissue grafts possessing cartilage-like compressive behavior, gradient biochemical microenvironment, stratified distribution of human marrow stromal cells (hMSC), and enhanced surface bonding affinity to subchondral bone for the reconstruction of full thickness articular cartilage defects. Three specific aims are developed. In Aim 1, we will test the hypothesis that chondroitin sulfate-mimicking (CS-M) polyelectrolyte fiber meshes can be fabricated to retain and release exogenous chondrogenic and osteogenic growth factors to induce chondrogenic and osteogenic differentiation of hMSC in culture, respectively. In Aim 2, we will test the hypothesis that chondrogenic and osteogenic CS-M fiber meshes pre-seeded with hMSC cells can be laminally encapsulated in photo-crosslinked hydrogel to create composite AC graft with cartilage-like compressive behavior, stratified zonal cellular distribution, and chondrogenic-to-osteogenic gradient biochemical microenvironment across the thickness of the composite graft. In Aim 3, we will test the hypothesis that the surface of the AC graft can be covalently functionalized with small molecule hydroxyapatite (HA)-binding ligands to enhance the graft bonding to subchondral bony tissue. The successful execution of the proposed project will contribute to the development of a novel strategy for the clinical treatment or replacement of AC tissues severely damaged due to chronic diseases, aging, trauma and congenital deformity. PUBLIC HEALTH RELEVANCE: Traumatic injuries and age-related degenerative diseases associated with articular cartilage can result in significant patient morbidity and lead to the development of osteoarthritis. The Centers for Disease Control and Prevention estimates that nearly 67 million (25%) of US adults will have clinically-diagnosed arthritis by 2030, making it the nation's leading cause of disability. Because of the avascular nature and limited potential for growth and self-repair, articular cartilage tissue damages are particularly challenging to repair. Tissue engineered cartilage constructs hold great promise in the clinical treatment or replacement of severely diseased (e.g. end-stage osteoarthritic) cartilage tissues. The successful development of viable synthetic cartilage constructs has significant social and economic implications, and contributes to improving the musculoskeletal health of the general population.